The present invention relates to methods of treating bacterial infections.
The ability of many bacterial infections to remain dormant but still viable and capable of causing disease is a major problem in the treatment and control of bacterial infections. For example, a useful treatment for M. tuberculosis must be effective against four different populations of tubercle bacilli within a single individual: a) rapidly growing extracellular and intracellular bacilli, b) bacilli within macrophages in an acidic environment, c) slow growing bacilli within caseous material at a neutral pH, and d) dormant bacilli. The dormant populations are not generally susceptible to conventional drug treatment regimens. For example, conventional drug treatment will kill actively growing M. tuberculosis within days, but months of therapy are needed to fully eliminate the dormant bacilli. If therapy is stopped too soon, the remaining dormant bacilli can be re-activated, leading to development of active, communicable disease.
Rifamycin-class antibiotics (e.g., rifampin, rifabutin, rifapentine, rifalazil, and rifaximin) are often the drug of choice for the treatment of various bacterial infections. To prevent the spontaneous development of resistant bacterial strains, rifamycin-class antibiotics are often given in combination with other antibacterial drugs (e.g., isoniazid, pyrazinamide, ethambutol, or streptomycin). For example, rifampin and isoniazid given in combination for nine months is a standard therapy for M. tuberculosis infections.
Rifamycin-class antibiotics are potent inhibitors of prokaryotic DNA-dependent RNA polymerase, with little activity against the equivalent mammalian enzymes. This group of antibacterial agents consists of compounds that are composed of aromatic rings linked by an aliphatic bridge.
One rifamycin-class antibiotic is rifalazil. Although rifalazil was found to be effective against mycobacterium species, it has never been used as a therapeutic agent for treatment of mycobacterial diseases because at the daily dose regimen which was believed to be necessary to its efficacious antibacterial activity, rifalazil caused severe adverse reactions, including flu-like symptoms with severe headache, malaise, fever, back pain, myalgia, chills, dizziness, nausea, vomiting, body pain, and weakness. Additionally, the daily administration of rifalazil resulted in changes in blood cell counts, particularly in decrease of white blood cell count (leukopenia), absolute neutrophil count, and platelet count, as well as in decreased blood hemoglobin.
More recently, a once or twice-a-week dose regimen was found to be efficacious against mycobacterium species, as described in U.S. Pat. No. 6,316,433, hereby incorporated by reference. It was also found that a once-or twice-a-week dosing regimen reduced, but did not eliminate, the incidence of adverse reactions. Clinical trials employing a twice-a-week dosing regimen demonstrated a clear dose-related incidence in the number and severity of adverse reactions. The predominate adverse reaction was development of “flu-like” symptoms.
Similar adverse reactions have been reported for other rifamycin-class antibiotics. Adverse reactions to rifampin are described, for example, by Martinez et al., Medicine (Baltimore) 78:361 (1999). Many of the adverse reactions induced by rifampin have been considered allergic in origin. For example, the flu-like syndrome appears to be caused by immune complexes, although their athogenetic mechanisms are not fully elucidated.